Applications of minimally invasive multimodal telemetry for continuous monitoring of brain function and intracranial pressure in macaques with acute viral encephalitis.

Abstract

49Alphaviruses such as Venezuelan equine encephalitis virus (VEEV) and Eastern equine encephalitis 50 virus (EEEV) are arboviruses that can cause severe zoonotic disease in humans. Both VEEV and EEEV are 51 highly infectious when aerosolized and can be used as biological weapons. Vaccines and therapeutics are 52 urgently needed, but efficacy determination requires animal models. The cynomolgus macaque (Macaca 53 fascicularis) provides a relevant model of human disease, but questions remain whether vaccines or therapeutics 54 can mitigate CNS infection or disease in this model. 55 The documentation of alphavirus encephalitis in animals relies on traditional physiological biomarkers 56 and behavioral/neurological observations by veterinary staff; quantitative measurements such as 57 electroencephalography (EEG) and intracranial pressure (ICP) can recapitulate underlying encephalitic 58 processes. We detail a telemetry implantation method suitable for continuous monitoring of both EEG and ICP 59 in awake macaques, as well as methods for collection and analysis of such data. We sought to evaluate whether 60 changes in EEG/ICP suggestive of CNS penetration by virus would be seen after aerosol exposure of naïve 61 macaques to VEEV IC INH9813 or EEEV V105 strains compared to mock-infection in a cohort of twelve adult 62 cynomolgus macaques. 63 Data collection ran continuously from at least four days preceding aerosol exposure and up to 50 days 64 thereafter. EEG signals were processed into frequency spectrum bands (delta: [0.4 -4Hz); theta: [4 -8Hz); 65 alpha: [8-12Hz); beta: [12-30] Hz) and assessed for viral encephalitis-associated changes against robust 66 background circadian variation while ICP data was assessed for signal fidelity, circadian variability, and for 67 meaningful differences during encephalitis. Results indicated differences in delta, alpha, and beta band 68 magnitude in infected macaques, disrupted circadian rhythm, and proportional increases in ICP in response to 69 alphavirus infection. This novel enhancement of the cynomolgus macaque model offers utility for timely 70 determination of onset, severity, and resolution of encephalitic disease and for the evaluation of vaccine and 71 therapeutic candidates. 72 3 73 Introduction 74 Alphaviruses, a genus of the family Togaviridae, are a group of linear, non-segmented positive-sense single-75 stranded RNA arboviruses found in many regions of the world. "New World" alphaviruses can invade the central 76 nervous system (CNS) and cause severe encephalitis which can be diagnosed by fever, brain swelling, and 77 neurological symptoms such as seizures and a diffuse slowing of brain activity across the physiologically relevant 78 electroencephalography (EEG) frequency spectra (1, 2). While Venezuelan equine encephalitis virus (VEEV) is 79 only rarely lethal in humans, North American strains of Eastern equine encephalitis virus (EEEV) have a high 80 mortality rate in confirmed cases (estimates range from 30-70% between outbreaks) and a high percentage of 81 sur...

Bunyavirales: Scientific Gaps and Prototype Pathogens for a Large and Diverse Group of Zoonotic Viruses

“…For phenuiviruses that have been tested in non-human primate species like macaques, the resulting disease is typically mild (transient viremia, modest changes in blood chemistry, mild/moderate fever) unless the virus is administered intranasally or by aerosol inhalation [13,14,24]. Advancements in continuous radiotelemetry monitoring allow measurement of subtle changes in body temperature, electrocardiography (EKG), electroencephalography (EEG), and intracranial pressure in animals that survive with mild illness [25][26][27][28][29][30]. These physiological changes, even in mild disease, can be used to statistically evaluate the efficacy of vaccines and therapeutics.…”